Using modern methods for synthesizing long DNAs, and using computer algorithms, we have recently synthesized several totally novel variants of polio virus in vitro from oligonucleotides, and we have converted these nucleic acids into infectious virus. These viruses preserve the exact protein coding capacity of wild- type polio, but use synonymous codons in various ways to target translation. Two of the viruses were designed to have poor codon bias, or poor codon pair bias, respectively, and both of these viruses were inviable (i.e., cannot form plaques on cultured cells). Here, we seek to understand exactly why the altered viruses are attenuated;to find ways of generating still other, novel polio viruses attenuated to predictable extents;and to extend this approach of synthesizing predictably-attenuated viruses to other classes of viruses. The most important longer term implication of these studies is that the predictable synthesis of attenuated virus should provide a rapid, safe, inexpensive, general and reliable method of creating the raw material for viral vaccines. In principle, vaccines could be created quickly even for very poorly characterized viruses, as long as a nucleic acid sequence is available. PUBLIC HEALTH RELEVANCE: Vaccination has been humankind's main most robust defense against viral disease. We describe an entirely novel and rapid method to generate anti-virus vaccine candidates that might prove applicable to most if not all human pathogenic viral systems.